Chronic immune activation persists in a subset of HIV-infected individuals who are virally suppressed. The consequences of this activation include cognitive impairment, cardiovascular disease and metabolic abnormalities. While a functioning immune response is important to maintain good health, continued activation can be detrimental. Our work has concentrated on monocyte activation in HIV infection and the initiation as well as consequences of chronic immune activation, including cognitive impairment and downstream cellular effects. Interferon alpha (IFN?) and lipopolysaccharide (LPS) from HIV infection activate monocytes that release exosomes, which are membrane bound nanoparticles that contain functional proteins, mRNA and abundant small noncoding microRNAs (miR). These exosomes alone can enter and influence recipient cells. We have characterized the exosomes from activated monocytes and identified miRs that influence immune activation associated with HIV infection. Our overall hypothesis is that targeted exosomes carrying specific antagomiRs will decrease peripheral activation and may decrease HIV infection by silencing activated monocytes. This proposal will engineer exosomes targeted to CD16+ monocytes and containing antagomiRs to silence the activation associated with several miRs that cause downstream brain and cardiovascular inflammation. We will utilize a functional in vitro assay to confirm silencing. Once we identify antagomiRs that can effectively silence the inflammatory response we will use these targeted exosomes in a humanized HIV mouse model and evaluate the in vivo response.